期刊
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
卷 19, 期 -, 页码 5210-5224出版社
ELSEVIER
DOI: 10.1016/j.csbj.2021.09.009
关键词
Intrinsically disordered regions; Multi-domain proteins; SMAD; Transcription factor; TGF beta signaling
资金
- Spanish MINECO [BFU2014-53787-P, BFU2017-82675-P]
- IRB Barcelona
- BBVA Foundation
- Horizon 2020 Programme
- iNEXT program (grant SMAD4 MH2 domain) [7192]
- FCT -Fundacao para a Ciencia e a Tecnologia, I.P., Project MOSTMICRO-ITQB [UIDB/04612/2020, UIDP/04612/2020]
- FEDER Funds through COMPETE 2020 [0145-FEDER-007660]
- CERCA Programme of the Catalan Government
- Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Centres of Excellence Severo Ochoa award
- Fundacao para a Ciencia e a Tecnologia, Ministerio da Ciencia, Tecnologia e Ensino Superior [CEECIND/01443/2017]
- Stimulus of Scientific Employment
The study unravels the structures of SMAD4 and SMAD2 proteins, revealing that they both have mixed architecture of globular domains and flexible linkers defining a new dimension of regulation. SMAD4FL is monomeric, while SMAD2FL exists in different monomer-dimer-trimer states driven by interactions of the MH2 domains. The study proposes that SMAD2FL dimers are key building blocks for the quaternary structures of SMAD complexes.
SMAD transcription factors, the main effectors of the TGFO (transforming growth factor O) network, have a mixed architecture of globular domains and flexible linkers. Such a complicated architecture precluded the description of their full-length (FL) structure for many years. In this study, we unravel the structures of SMAD4 and SMAD2 proteins through an integrative approach combining Small-angle X-ray scattering, Nuclear Magnetic Resonance spectroscopy, X-ray, and computational modeling. We show that both proteins populate ensembles of conformations, with the globular domains tethered by disordered and flexible linkers, which defines a new dimension of regulation. The flexibility of the linkers facilitates DNA and protein binding and modulates the protein structure. Yet, SMAD4FL is monomeric, whereas SMAD2FL is in different monomer-dimer-trimer states, driven by interactions of the MH2 domains. Dimers are present regardless of the SMAD2FL activation state and concentration. Finally, we propose that SMAD2FL dimers are key building blocks for the quaternary structures of SMAD complexes. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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